HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mahalanabis, D. Articles by Khaled, M. A Search for Related Content PubMed PubMed Citation Articles by Mahalanabis, D. Articles by Khaled, M. A Agricola Articles by Mahalanabis, D. Articles by Khaled, M. A

Randomized, double-blind, placebo-controlled clinical trial of the efficacy of treatment with zinc or vitamin A in infants and young children with severe acute lower respiratory infection^1,2,3

¹ From the Society for Applied Studies, Kolkata, India (DM and SG); the BC Roy Memorial Hospital for Children, Kolkata, India (ML, DP, and AG); the ICDDR-B, Dhaka, Bangladesh (MAW); and the University of Alabama at Birmingham (MAK).

² Supported by a research grant from Nutricia Research Foundation, The Hague.

³ Reprints not available. Address correspondence to D Mahalanabis, Society for Applied Studies, 108 Manicktala Main Road, Flat-3/21, Kolkata 700054, India. E-mail: dmahalanabis{at}vsnl.com.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background: Acute lower respiratory infection (ALRI) is a leading cause of childhood death. Zinc supplementation prevents ALRI. Vitamin A supplementation reduces childhood mortality, but its benefit concerning ALRI-specific mortality is unproven.

Objective: The objective was to evaluate the effect of zinc and vitamin A on the clinical recovery of children with severe ALRI.

Design: In a controlled trial with a factorial design, 153 children aged 2-24 mo who were hospitalized with severe ALRI were randomly assigned to receive 10 mg zinc as acetate (twice daily for 5 d) plus vitamin A placebo, 10 000 µg retinol equivalents vitamin A (twice daily for 4 d) plus zinc placebo, zinc plus vitamin A, or zinc and vitamin A placebos. The main outcome variable was the time for resolution of very ill status; other outcomes were resolution of fever, tachypnea, and feeding difficulty.

Results: Recovery rates from very ill status and from fever in zinc-treated boys were 2.6 times (P = 0.004) and 3 times (P = 0.003) those in non-zinc-treated children; feeding difficulty and tachypnea were not significantly different between groups after an adjusted analysis. Recovery rates were not significantly different between groups on the basis of vitamin A treatment. At discharge, serum zinc was 6.06 µmol/L higher (P = 0.001) in the zinc-treated children, and serum retinol was 0.387 µmol/L higher (P = 0.001) in the vitamin A-treated children.

Conclusion: Zinc treatment significantly reduces duration of fever and very ill status in boys, but not in girls, with severe ALRI. Vitamin A treatment of children with severe ALRI had no significant beneficial effect.

Key Words: Zinc • vitamin A • acute lower respiratory infection • ALRI • therapy • sex effect • clinical trial

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Acute respiratory infection is an important cause of morbidity globally and of mortality in children in developing countries (1). Several intervention studies that used a case management algorithm to treat children in developing countries with acute lower respiratory infection (ALRI) showed that mortality specific to acute respiratory infection decreased by an average of 42% and overall mortality by 23% (1). Therefore, any improvement in the case management of ALRI in children may contribute to a further reduction in mortality specific to acute respiratory infection.

Zinc supplementation has already been shown to benefit children with acute and persistent diarrhea by reducing the duration and severity of episodes (2, 3). Furthermore, zinc supplementation was shown to prevent pneumonia in children in developing countries (4). Zinc as a micronutrient plays a key role at the catalytic sites of a wide range of enzymes and is critical to human growth, metabolism, and immune function (5). The diets of children in many developing countries are often deficient in zinc and a high phytate:zinc ratio in their diet reduces zinc bioavailability (6).

Periodic supplementation of children with vitamin A was shown to substantially reduce overall childhood mortality (7-9). Furthermore, large-dose vitamin A supplementation during illness has been shown to reduce mortality (10-12), the severity of illness (11-13), and the duration of pneumonia (11, 12) in children with measles and to possibly reduce significantly the number of persistent diarrhea episodes in children with acute diarrhea (3). The results of trials in children with ALRI or pneumonia who were treated with vitamin A are conflicting (14-23). In general, no benefit or modestly adverse effect in well-nourished children and some benefit in malnourished children have been reported. In the current study, we examined whether infants and young children hospitalized with severe ALRI benefit from the administration of zinc or large doses of vitamin A. The main objective was to evaluate the effect on clinical recovery of the addition of zinc or large doses of vitamin A to the standard treatment for severe ALRI and pneumonia in infants and young children.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Children aged 2-24 mo of either sex who were sufficiently ill to be admitted to the BC Roy Memorial Hospital for Children, Kolkata (formerly Calcutta), India with a clinical diagnosis of severe ALRI were considered for inclusion in the study. This hospital provides free treatment to largely urban and periurban poor. The physician diagnosed ALRI on the basis of the presence of cough and fast breathing (respiratory rate >50/min for children aged 2-11 mo and >40/min for children aged 12-24 mo) or lower chest indrawing (1); severe ALRI was diagnosed when ALRI was associated with either 1) cough combined with crepitation or bronchial breathing on auscultation or with 2) one of the following severity indicators: inability to drink or feed, marked lethargy or irritability, nasal flare, or drowsiness. Children with severe ALRI, as defined above, were included in the study. Children with obvious marasmus or edema, with severe nonrespiratory infection (eg, meningitis, bloody diarrhea, congenital heart disease, or another gross congenital malformation) were excluded. After informed consent was obtained from the parents of eligible children, the children were entered into the study. The study protocol was approved by the Ethical Review Committee of the Society for Applied Studies. Patient recruitment took place from 25 March 1997 to 19 December 1998.

A factorial treatment trial design was used to evaluate the role of zinc or vitamin A supplementation as adjunct therapy of severe ALRI in infants and young children. This enabled us to make 2 treatment comparisons in one trial with a smaller number of patients in the trial. For 2 independent comparisons, patients were randomly assigned into 4 groups to receive supplements of 1) zinc acetate (10 mg elemental Zn twice daily for 5 d) plus a placebo for vitamin A, 2) vitamin A as retinyl palmitate [10 000 µg retinol equivalents (RE) twice daily for 4 d] plus a placebo for zinc, 3) zinc plus vitamin A according to the above schedule, or 4) placebo for zinc and for vitamin A. The effect of zinc was evaluated by comparing the children who received zinc (groups 1 and 3) with those who did not (groups 2 and 4). The effect of vitamin A was evaluated by comparing the children who received vitamin A (groups 2 and 3) with those who did not (groups 1 and 4). The design ensured that when one comparison was made, the distribution of the other intervention was balanced. However, we adjusted for the treatment effect of either supplement and their interaction in an appropriate multivariate analysis.

Randomization
A master randomization schedule was prepared by a person not associated with the study who used permuted blocks of random numbers. The medicine bottles and identical placebo were prepared by a pharmaceutical manufacturer under the supervision of a qualified pharmaceutical chemist acting as a consultant on our behalf. Random samples of the bottled mixtures were tested by atomic absorption spectrophotometry for zinc concentration and by HPLC for retinol. Randomization was incorporated in the serially numbered bottles containing drug or placebo by a pharmaceutical chemist not involved with the study. The serial number of the bottle corresponded with the serial number of the patient.

Intervention
A zinc acetate mixture containing 10 mg elemental Zn or placebo mixture was given twice daily for each day of stay for 5 d. Vitamin A (10 000 µg RE as retinyl palmitate) was given as a water miscible preparation twice daily for 4 d. Placebo for zinc consisted of the syrup base used for the zinc mixture, which was appropriately modified to give a taste similar to the zinc mixture. A trace amount of a widely used dry edible fruit (myrobalan), with an astringent taste, was added to the zinc placebo. Placebo for vitamin A was the syrup base used for vitamin A palmitate. Both the participants and those administering and evaluating the patients were unaware of the treatment allocation. All patients received a standard schedule of treatment for severe ALRI and associated problems that was based on the existing practice of the hospital, which included antibiotics, bronchodilators, and oxygen as required. All children were treated with a combination of cloxacilin and gentamycin parenterally as first-line antibiotic treatment. If no improvement was observed in 48 h or if the children's conditions deteriorated during the course of treatment, the physicians made a clinical decision to change the antibiotic regimen to cefotaxime or ceftriaxone parenterally.

Sample size
On the basis of the consensus of the hospital pediatricians, 50% of the patients were expected to achieve "clinically cured" or "much improved" status after 4 d of treatment. With zinc as an adjunct therapy, we expected 75% of the children to achieve this status as judged by the clinician. The calculated number in each group (with 80% power and a 5% significance level) would be 76 children, assuming a withdrawal rate of 8% (24). On the basis of similar assumptions for the proportion of patients in whom tachypnea or fever would have resolved after 4 d of treatment, the calculated sample sizes would be similar. Similar assumptions were made for the effect of vitamin A. A total of 152 patients was the estimated sample size.

Clinical evaluation
Before the study began, several briefing meetings were conducted with the pediatricians. It was decided that, in addition to documenting standard clinical features, the pediatricians would record their clinical judgement as to whether a child had attained a clinically cured or much improved status based on the following criteria: 1) alertness and general well being, 2) resolution of respiratory distress, 3) how well the infant feeds, and 4) resolution of fever and tachypnea (as defined later). The major outcome variable was the time taken for this composite illness indicator to resolve. No scoring system was used, and it was agreed that the introduction of a fresh scoring system would not be worthwhile. Clinical features were evaluated and recorded twice daily, in the morning and evening, by the 3 study pediatricians, who were unaware of the treatment allocation. Other outcome variables were also examined: the time for the resolution of tachypnea (ie, respiratory rate >50/min in 12 mo and >40/min in >12 mo), fever (ie, skin temperature >98 °F, or 36.7 °C), and feeding difficulty (as judged by the mother or caregiver staying with the patient).

Analysis
Data were recorded on standard forms, entered into a microcomputer, and edited with the use of EPI INFO version 6.03 software (Centers for Disease Control and Prevention, Atlanta, and the World Health Organization, Geneva). The major objective of the study was to evaluate the effect of zinc or vitamin A on the clinical course of illness due to pneumonia in infants and young children. We therefore used survival (time to an event) analysis techniques to compare the duration of the illness indicators, which also permitted us to adjust for censored data. The clinical illness indicators used were the time to resolution of 1) very ill clinical status as judged by the pediatrician, 2) fever, 3) feeding difficulty or inability to feed, and 4) tachypnea. Indicator 1, the main outcome measure, is a composite indicator that is based on the clinician's assessment of alertness, breathing difficulty, ability to feed well, fever, and tachypnea. Prognostic factors like age, sex, treatment with zinc for evaluating the effect of vitamin A, treatment with vitamin A for evaluating the effect of zinc, and any significant interaction between zinc and vitamin A supplementation were adjusted for, with the use of Cox proportional hazards regression analysis. The software program STATA release 7.0 (Stata Corporation, TX) was used for survival analysis. The median duration of illness indicators were obtained from the Kaplan-Meier product-limit estimate of the survivor function, and the SE of the median was calculated by the method of Klein and Maeschberger (25). The hazards ratio indicates the ratio of recovery rates from the illness indicators in supplemented to unsupplemented children at any time point during the study; values >1 are associated with the probability of the duration of illness indicators being shorter in the zinc- or vitamin A-supplemented children.

We further examined the median duration of the illness indicators stratified by sex and noted that sex is an effect modifier for zinc effect but not for vitamin A. We, therefore, also analyzed the treatment effect for zinc in boys and girls separately. All analyses were done on an intention-to-treat basis. Results of the interaction tests involving sex are given in Results.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Two hundred twenty-two children were assessed for eligibility, and 153 children were enrolled (Figure 1). One child in the placebo group withdrew at 50 h, and one child in the vitamin A group withdrew at 63 h. One child in the zinc and vitamin A group died at 15 h. Thirty-nine children in the zinc group and 37 in each of the other 3 groups completed 5 d of observation in the hospital.

View larger version (25K): [in this window] [in a new window]   FIGURE 1.. Flow chart for patient recruitment.

Table 1

Table 2

Table 3

Table 4

View larger version (19K): [in this window] [in a new window]   FIGURE 2.. Survival curves for the resolution of 2 illness indicators in boys who received zinc with or without vitamin A (Z, n = 50) compared with those who did not receive zinc (N, n = 47), determined with the use of Cox proportional hazards regression analysis and adjusted for the interaction between zinc and vitamin A and for vitamin A (A: very ill status, P = 0.004; B: fever, P = 0.003) and in boys who received zinc only (Z1, n = 25) compared with those who received placebo only (P, n = 21), determined with Kaplan-Meier product-limit estimates (C: very ill status, P = 0.006; D: fever, P = 0.002). The patterns were similar for feeding difficulty and tachypnea (data not shown).

The incidence of adverse events and a need to change antibiotics by treatment group are shown in Table 5. Diarrhea was associated with vitamin A supplementation (P = 0.028) but not with zinc supplementation (rate ratio: 0.25; 95% CI: 0.23, 2.16). Antibiotic change tended to be more common in the vitamin A-supplemented children (rate ratio = 3.55; P = 0.098). Any adverse effect or a need for antibiotic change was higher in the vitamin A-supplemented children (rate ratio = 3.8; 95% CI: 1.32, 10.93; P = 0.006). Bulging fontanelle occurred in 2 children supplemented with vitamin A and zinc and in 1 child supplemented with zinc but not with vitamin A.

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

Zinc treatment of pneumonia
Zinc deficiency is thought to be common in children in developing countries whose diets are low in animal products and high in phytate (6). Repeated episodes of diarrhea exacerbate zinc deficiency because of the loss of zinc in stool (26). Unlike some other micronutrients of public health importance, zinc deficiency is not associated with specific clinical features, and no reliable biomarkers of deficiency are available to identify populations with mild-to-moderate zinc deficiency. In the current study, zinc treatment significantly increased serum zinc concentrations in infants and children with severe ALRI compared with controls.

An analysis of the data resulted in an unexpected finding. Sex appeared to be a strong effect modifier in that zinc treatment showed a clear benefit in boys but not in girls, in whom the effect may have even been adverse. Taking advantage of the factorial study design, we found additional support for the beneficial effect of zinc treatment in boys with severe ALRI through a direct comparison of boys who received zinc only with boys who received placebo only. The rate of adverse events or a need for a change in antibiotic was not higher in children supplemented with zinc than in children not supplemented with zinc.

In a pooled analysis (4) of the results of 4 zinc supplementation trials that evaluated the effect of zinc supplementation on the prevention of diarrhea and pneumonia in children in developing countries, in whom morbidity was assessed concurrently, zinc-supplemented children had a 41% reduced rate of pneumonia (95% CI: 17%, 59%). In a trial in Bangladesh (27), in which the children were supplemented with zinc for 14 d only and morbidity was assessed over the subsequent 6 mo, zinc supplementation showed no favorable effect on the incidence and prevalence of pneumonia. We note, however, that zinc is not stored in the body in the same way that iron or vitamin A is. We were unable to locate any trial of zinc supplementation in children with pneumonia or ALRI to compare our results.

The beneficial results of zinc supplementation in boys with pneumonia were based on a subgroup analysis and, therefore, require confirmation. We also acknowledge our inability to adequately explain why only boys with pneumonia benefited from treatment with zinc. The results should encourage investigators of earlier zinc supplementation trials in children for the prevention of diarrhea and pneumonia to examine their data for any sex effect. Mean serum zinc concentrations at admission were similar in boys and girls. Mean serum zinc concentrations at discharge in both the zinc-supplemented and unsupplemented children showed a similar increase in boys and girls (data not shown). Severity of illness was similar in boys and girls at admission.

Vitamin A treatment of severe ALRI
As stated earlier, trials of vitamin A treatment in both developing and developed countries showed conflicting results (14-23). In general, no benefit and even adverse effects were reported. Some studies reported a benefit of vitamin A supplementation in malnourished children. The current study was conducted in infants and young children hospitalized with severe disease due to ALRI. Serum retinol concentrations at admission were low, which may indicate both a deficiency and a consequence of severe infection. Apart from an acute phase response after infection, retinol may also be lost in urine, particularly in febrile illness (28). Serum retinol concentrations improved in both supplemented and unsupplemented children. However, serum retinol values at discharge in the vitamin A-supplemented children were significantly higher than those in the unsupplemented children, which suggests an underlying vitamin A deficiency in the study population.

In the current study, as in the earlier trials mentioned (14-23), vitamin A treatment of infants and young children hospitalized with pneumonia did not render any worthwhile benefit. Furthermore, the rate of adverse events particularly diarrhea or a need to change antibiotics due to lack of clinical response or deterioration was higher in vitamin A treated children compared with no-vitamin A children. The total dose of vitamin A was relatively large, which may partly explain some of the adverse events. We note, however, that there is a slightly increased incidence of pneumonia in boys in developing countries (29). The results of the current study, however, do not help explain why vitamin A supplementation of children in developing countries substantially reduces all-cause mortality (7).

We conclude that zinc treatment significantly reduces the duration of fever and of a composite illness indicator (ie, very ill status) in boys with ALRI, but has no significant effect in girls with severe ALRI. Vitamin A treatment of children with severe ALRI has no significant beneficial effect and was associated with adverse events, particularly diarrhea. Zinc treatment increased mean serum zinc concentrations, and vitamin A treatment increased mean serum retinol concentrations in this population, who had low concentrations at baseline.

	ACKNOWLEDGMENTS

 
We thank Anup Mondal (Superintendent), the doctors and healthcare workers of BC Roy Memorial Hospital for Children, and ML Chakrabarti of Kothari (Medical Research Centre, Kolkata, India) for their assistance with the conduct of this study; Zakir Hussain for data management and analysis; and Subodh Karmakar for typing and editing the manuscript.

DM was responsible for designing the study, analyzing the data, and writing and interpreting the manuscript. ML, DP, and AG took part in designing the study, evaluating the illness indicators, and writing and interpreting the manuscript. SG took part in designing the study and collecting and analyzing the data. MAK took part in designing the study, in the quality control of laboratory tests, and in writing and interpreting the manuscript. MAW was responsible for analyzing the serum zinc and vitamin A concentrations and interpreting the results. None of the authors had any financial or personal interest in the foundation supporting this research.

	REFERENCES

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Stansfield SK, Shepard DS. Acute respiratory infection. In: Jamison DT, Mosley WH, Measham AR, Bourdilla JL, eds. Disease control priorities in developing countries. New York: Oxford University Press (for World Bank), 1993:67-90.
2. Zinc Investigators Collaborative Group. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: pooled analysis of randomized controlled trials. Am J Clin Nutr 2000;72:1516-22.[Abstract/Free Full Text]
3. Mahalanabis D, Bhan MK. Micronutrients as adjunct therapy of acute illness in children: impact on the episode outcome and policy implications of current findings. Br J Nutr 2001;85:S151-8.
4. Zinc Investigators Collaborative Group. Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. J Pediatr 1999;155:689-97.
5. Aggett PJ, Comerford JG. Zinc and human health. Nutr Rev 1995;53:S16-22.[Medline]
6. Gibson RS, Ferguson EL, Lehrfeld J. Complementary foods for infant feeding in developing countries: their nutrient adequacy and improvement. Eur J Clin Nutr 1998;52:764-70.[Medline]
7. Beaton GH, Martarell R, L'Abbe KA, Edmonston B, McCabe G, Ross AC. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. SCN News 1993;9:17-23.
8. Glasziou PP, Mackerras DEM. Vitamin A supplementation in infectious diseases: a meta-analysis. BMJ 1993;306:366-70.[Medline]
9. Fawzi WW, Chalmers TC, Herrera MG, Mosteller F. Vitamin A supplementation and child mortality, a meta-analysis. JAMA 1993;269:899-903.
10. Barclay AJG, Foster A, Sommer A. Vitamin A supplements and mortality related to measles: a randomized clinical trial. BMJ 1987;294:294-6.[Medline]
11. Hussey GD, Klein M. A randomized controlled trial of vitamin A in children with severe measles. N Engl J Med 1990;323:160-4.[Abstract]
12. Madhulika, Kabra SK, Talati A. Vitamin A supplementation in post-measles complications. J Trop Pediatr 1994;40:305-7.[Abstract/Free Full Text]
13. Coutsoudis A, Broughton M, Coovadia HM. Vitamin A supplementation reduces measles morbidity in young African children: a randomized, placebo-controlled, double-blind trial. Am J Clin Nutr 1991;54:890-5.[Abstract/Free Full Text]
14. Kjolhede CL, Chew FJ, Gadomsks AM, Marroquin DP. Clinical trial of vitamin A as adjuvant treatment for lower respiratory tract infections. J Pediatr 1995;126:807-12.[Medline]
15. Quinlan KP, Hayani KC. Vitamin A and respiratory syncytial virus infection. Arch Pediatr Adolesc Med 1996;150:25-30.[Abstract]
16. Fawzi WW, Mbise R, Spiegelman D, Fataki M, Hertzmark E, Ndossi G. Vitamin A supplements and diarrheal and respiratory tract infections among children in Dar es Salaam, Tanzania. J Pediatr 2000;137:660-7.[Medline]
17. Nacul LC, Kirkwood BR, Arthur P, Morris SS, Magalhaes M, Find MCDS. Randomized, double blind, placebo controlled clinical trial of efficacy of vitamin A treatment in non-measles childhood pneumonia. BMJ 1997;13:1008-13.
18. Dowell S, Papic Z, Bresee JS, et al. Treatment of respiratory syncytial virus infection with vitamin A: a randomized, placebo-controlled trial in Santiago, Chile. Pediatr Infect Dis J 1996;15:782-6.[Medline]
19. Sempertegui F, Estrella B, Camaniero V, et al. The beneficial effects of weekly low-dose vitamin A supplementation on acute lower respiratory infections and diarrhea in Ecuadorian children. Pediatrics [serial online] 1999;104:e1.Internet: http://www.pediatrics.org/cgi/content/full/104/1/e1 (accessed 5 December 2003).
20. Si NV, Grytter C, Vy NN, Hue NB, Pedersen FK. High dose vitamin A supplementation in the course of pneumonia in Vietnamese children. Acta Pediatr 1997;86:1052-5.[Medline]
21. Bresee JS, Fischer M, Dowell SF, et al. Vitamin A therapy for children with respiratory syncytial virus infection: a multicenter trial in the United States. Pediatr Infect Dis J 1996;15:777-82.[Medline]
22. Fawzi WW, Mbise RL, Fataki MR, et al. Vitamin A supplementation and severity of pneumonia in children admitted to the hospital in Dar es Salaam, Tanzania. Am J Clin Nutr 1998;68:187-92.[Abstract]
23. Stephensen CB, Franchi LM, Hernandez H, Campos M, Gilman RH, Alvarez JO. Adverse effects of high-dose vitamin A supplements in children hospitalized with pneumonia. Pediatrics [serial online] 1998;101:e3.Internet: http://www.pediatrics.org/cgi/content/full/101/5/e1 (accessed 5 December 2003).
24. Pocock SJ. Clinical trials—a practical approach. New York: Wiley & Sons, 1983.
25. Klein JP, Maeschberger ML. Survival analysis techniques for censored and truncated data. New York: Springer, 1997:110-1.
26. Castillo-Duran C, Vial P, Uauy R. Trace mineral balance during acute diarrhea in infants. J Pediatr 1988;113:452-7.[Medline]
27. Rahman MM, Vermund SH, Wahed MA, Fuchs GJ, Bqeui AH, Alvarez JO. Simultaneous zinc and vitamin A supplementation in Bangladeshi children: randomized double blind controlled trial. BMJ 2001;323:314-8.[Abstract/Free Full Text]
28. Mitra AK, Alvarez NO, Stephensen CB. Increased urinary retinol loss in children with severe infections. Lancet 1998;351:1033-4.[Medline]
29. Selwyn BJ, on behalf of the Coordinated Data Group of BOSTID Researchers. The epidemiology of acute respiratory tract infection in young children: comparison of findings from several developing countries. Rev Infect Dis 1990;12(suppl):5870-88.

This article has been cited by other articles:

				C. L Coles, A. Bose, P. D Moses, L. Mathew, I. Agarwal, T. Mammen, and M. Santosham Infectious etiology modifies the treatment effect of zinc in severe pneumonia Am. J. Clinical Nutrition, August 1, 2007; 86(2): 397 - 403. [Abstract] [Full Text] [PDF]

				W. Van Molle, M. Van Roy, T. Van Bogaert, L. Dejager, P. Van Lint, I. Vanlaere, K. Sekikawa, G. Kollias, and C. Libert Protection of Zinc against Tumor Necrosis Factor Induced Lethal Inflammation Depends on Heat Shock Protein 70 and Allows Safe Antitumor Therapy Cancer Res., August 1, 2007; 67(15): 7301 - 7307. [Abstract] [Full Text] [PDF]

				S. Howie, S. M. Zaman, O. Omoruyi, R. Adegbola, and A. Prentice Severe pneumonia research and the problem of case definition: the example of zinc trials Am. J. Clinical Nutrition, January 1, 2007; 85(1): 242 - 243. [Full Text] [PDF]

				K M. Hambidge Zinc and pneumonia Am. J. Clinical Nutrition, May 1, 2006; 83(5): 991 - 992. [Full Text] [PDF]

				A. Bose, C. L Coles, Gunavathi, H. John, P. Moses, P Raghupathy, C. Kirubakaran, R. E Black, W A. Brooks, and M. Santosham Efficacy of zinc in the treatment of severe pneumonia in hospitalized children <2 y old Am. J. Clinical Nutrition, May 1, 2006; 83(5): 1089 - 1096. [Abstract] [Full Text] [PDF]

				E. Villamor and W. W. Fawzi Effects of Vitamin A Supplementation on Immune Responses and Correlation with Clinical Outcomes Clin. Microbiol. Rev., July 1, 2005; 18(3): 446 - 464. [Abstract] [Full Text] [PDF]

				Minerva BMJ, March 27, 2004; 328(7442): 776 - 776. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mahalanabis, D. Articles by Khaled, M. A Search for Related Content PubMed PubMed Citation Articles by Mahalanabis, D. Articles by Khaled, M. A Agricola Articles by Mahalanabis, D. Articles by Khaled, M. A